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Title: The potential role of the airway epithelium and novel therapeutic strategies in post-transplant obliterative bronchiolitis
Author: Murphy, Desmond Michael
ISNI:       0000 0001 3433 295X
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2008
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Long-term survival of lung transplant recipients is limited by development of chronic allograft rejection, manifesting as bronchiolitis obliterans syndrome (BOS), and affecting over 50% of patients surviving more than 5 years post transplant. Unfortunately, current strategies in the management of BOS have had limited impact on its development and progression. The histological lesion of BOS, obliterative bronchiolitis (OB), is characterised by bronchiolar epithelial activation, airway leukocyte infiltration and fibro-proliferation, leading to obliteration of bronchioles through deposition of collagen matrix. The bronchial epithelium is a major source of cytokines, chemokines and growth factors, which contribute to airway inflammation and the airway remodelling process of OB. In this study, I describe the methodology for successful culture of primary bronchial epithelial cells (PBECs) from lung allografts. The establishment of these PBECs has provided a platform to facilitate ex-vivo studies of potential epithelial involvement in the pathophysiology of OB. Using this model, I have shown the ability of IL-I7 (Interleukin-I7), TGF-p (Transforming Growth Factor Beta) and bacterial products to modulate epithelial production of mediators of airway inflammation and remodelling, consistent with the development of OB. Included in my thesis is a pilot study demonstrating that rescue therapy with the macrolide antibiotic, azithromycin resulted in a significant improvement in lung function in patients with BOS. I have also shown through a series of PBEC experiments the potential for azithromycin, simvastatin and phosphodiesterase-4 inhibition to decrease PBEC release of cytokines, chemokines and growth factors critical to airway inflammation and remodelling. The development of a reliable method for the culture of bronchial epithelial cells from lung allografts paves the way for dissecting the involvement of the bronchial epithelium in inflammation, remodelling and fibroproliferation in the transplanted airway. It may also help clarify the role of potential therapeutic agents in the prevention and management of DB in allograft recipients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available